PROJECT SUMMARY This project aims to design an innovative nanotherapeutic for treatment of synucleinopathies such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), or dementia with Lewy bodies (DLB). These age-related neurodegenerative diseases are characterized by the deposition and aggregation of the protein alpha-synuclein (ASYN). Chronic and excessive ASYN accumulation can cause the recruitment of microglia cells that play the important role of clearance of ASYN. Sustained activation of microglia compromises the normal degradation pathways of ASYN, leading to a cycle of internal ASYN aggregation and neuroinflammation. Thus targeting microglial cells is a potentially viable approach for treating ASYN related neurodegeneration. The central hypothesis is that that by regulating ASYN interactions with microglial receptors, intracellular aggregation of ASYN can be inhibited, and that the progression of synucleinopathy can be halted. We aim to develop nanotherapeutics by designing synthetic nanoparticles (NPs) composed of amphiphilic molecules that can molecularly target specific microglial scavenger receptors (SRs). SRs mediate the uptake of ASYN and also catalyze ASYN oligomerization. In Aim 1, we propose a novel design for the NPs such that the NPs can serve as binding partners to SRs along with ASYN, but once internalized within microglia, the active core region of these nanoparticles will be exposed, disrupting intracellular aggregation of ASYN. In Aim 2, we will also investigate the efficacy of delivering an antioxidant payload to counteract microglial activation and thus ameliorate the activation of the pro-inflammatory M1 microglial phenotype. The effects of the NPs on microglial ASYN uptake and intracellular aggregation will be evaluated in vitro and in vivo. In addition to decreasing ASYN aggregation, targeting microglial activation states by suppressing the harmful effects of M1 microglia or switching activation states to the neuroprotective M2 phenotype can provide therapeutic benefits in neurodegenerative diseases. The overall outcomes from this study will help to address the critical barriers of maintaining microglial clearance of ASYN and decreasing the inflammatory effects of classically activated microglia within synucleinopathies and other neurodegenerative diseases.